IL-21 peptides were first disclosed in WO 00/53761 as SEQ ID No: 2. The pro-peptide is a 161 amino acid residue peptide. For convenience, the sequence is repeated in the present application as SEQ ID No: 1. It was initially believed that the mature peptide was the peptide consisting of amino acids No. 33 to 162 of SEQ ID No: 1; however more recently (WO 2004/112703) it has been suggested that the mature peptide is, in fact, amino acids No. 30 to 162, which is disclosed as SEQ ID No: 11 with an additional N-terminal methionine in the present application.
IL-21 is a cytokine. Cytokines generally stimulate proliferation, differentiation and/or activation of cells of the hematopoietic lineage or participate in the immune and inflammatory response mechanisms of the body. The interleukins are a family of cytokines that mediate immunological responses by producing various cytokines, and they effect adaptive immunity to antigens. Mature T cells can be activated, i.e., by an antigen or other stimulus, to produce, for example, cytokines, biochemical signaling molecules, or receptors that further influence the fate of the T cell population.
Cytokines produced by the T cell have been classified as type 1 and type 2 (Kelso, A. Immun. Cell Biol. 76:300-317, 1998). Type 1 cytokines include IL-2, IFN-γ, LT-α, and they are involved in inflammatory responses, viral immunity, intracellular parasite immunity and allograft rejection. Type 2 cytokines include IL-4, IL-5, IL-6, IL-10 and IL-13, and they are involved in humoral responses, helminth immunity and allergic response. Shared cytokines between Type 1 and 2 include IL-3, GM-CSF and TNF-α. There is some evidence to suggest that Type 1 and Type 2 producing T cell populations preferentially migrate into different types of inflamed tissue.
Mature T cells can be activated, i.e., by an antigen or other stimulus, to produce, for example, cytokines, biochemical signaling molecules, or receptors that further influence the fate of the T cell population.
B cells can be activated via receptors on their cell surface including B cell receptor and other accessory molecules to perform accessory cell functions, such as production of cytokines and antibodies.
Natural killer (NK) cells have a common progenitor cell with T cells and B cells, and play a role in immune surveillance. NK cells, which comprise up to 15% of blood lymphocytes, do not express antigen receptors, and therefore do not use MHC recognition as requirement for binding to a target cell. NK cells are involved in the recognition and killing of certain tumor cells and virally infected cells. In vivo, NK cells are believed to require activation, however, in vitro, NK cells have been shown to kill some types of tumor cells via KIR ligand dependent activation.
In spite of the efficacy shown by IL-21 in the treatment of various diseases, there remains a need for variants of IL-21 with improved or alternative properties, such as activity, selectivity, stability, and circulation time or biological half-life, to fulfil medical needs.